Protein kinase C (“PKC”) is a key enzyme in signal transduction involved in a variety of cellular functions, including cell growth, regulation of gene expression, and ion channel activity. The PKC family of isozymes includes at least 10 different protein kinases that can be divided into at least three subfamilies based on their homology and sensitivity to activators. (See FIG. 1.) Each isozyme includes a number of homologous (“conserved” or “C”) domains interspersed with isozyme-unique (“variable” or “V”) domains. Members of the “classical” subfamily, α (SEQ ID NO:164), βI (SEQ ID NO:165), βII (SEQ ID NO:166) and γPKC (SEQ ID NO:167), contain four homologous domains (C1, C2, C3 and C4) and require calcium, phosphatidylserine, and diacylglycerol or phorbol esters for activation. Members of the “novel” subfamily, δ(SEQ ID NO:168), ε (SEQ ID NO:169), η (SEQ ID NO:170) and θPKC (SEQ ID NO:171), lack the C2 homologous domain and do not require calcium for activation. Finally, members of the “atypical” subfamily, ζ (SEQ ID NO:174) and λ/lPKC (SEQ ID NO:172), lack both the C2 and one-half of the C1 homologous domains and are insensitive to diacylglycerol, phorbol esters and calcium.
Individual isozymes of PKC have been implicated in the mechanisms of various disease states, including the following: cancer (alpha and delta PKC); cardiac hypertrophy and heart failure (beta I and beta II PKC) nociception (gamma and epsilon PKC); ischemia including myocardial infarction (delta and epsilon PKC); immune response, particularly T-cell mediated (theta PKC); and fibroblast growth and memory (zeta PKC).